Oxytocin receptors

Several human receptors for the neurohypophyseal hormones have been cloned and the sequences elucidated. The human V2 receptor for antidiuretic hormone presumably contains 371 amino acids and seven transmembrane segments and activates cycHc AMP (76). The oxytocin receptor is a classic G-protein-coupled type of receptor with a proposed membrane topography also involving seven transmembrane components (84). A schematic representation of the oxytocin receptor stmcture within the membrane is shown in Eigure 4 (85). 

Fig. 4. Representation of proposed topography of human oxytocin receptor (85) where CHO represents carbohydrate.

Gimpl G, Fahrenholz F (2001) The oxytocin receptor system structure, function, and regulation. Physiol Rev 81 629-683... 

TREATMENT OF PRETERM LABOUR The Role of Oxytocin in Labour Regulation of Oxytocin during Labour Regulation of the Oxytocin Receptor Experiences with Oxytocin Antagonists Selective OT or Mixed OT/Via Blockade ... 

The precise mechanisms triggering the onset of labour are unknown. There are many changes that occur while preparing the uterus and foetus for the onset of labour. However, it is clear that regulation of both oxytocin and the oxytocin receptor plays an important role in childbirth. 

Oxytocin and vasopressin are closely related peptides sharing seven out of nine amino acids. Vasopressin is able to bind to all vasopressin and oxytocin receptors with nanomolar affinity, whereas oxytocin has greater affinity for the oxytocin receptor than the vasopressin receptors. The affinity of the peptides for the receptors is shown in Table 7.1 (data from Mouillac et al. [20]). 

Oxytocin is required for lactation. Milk is initially secreted into small sacs (alveoli) within the mammary gland. These alveoli are surrounded by smooth muscle, which contract to eject the milk. The oxytocin receptor is the key receptor that mediates this ejection of the milk. 

The first non-peptide oxytocin antagonists, based on a spiropiperidine template, were described by Merck in 1992 [68-70]. The binding affinity data for key compounds from this series are summarised in Table 7.2. The initial screening hit, L-342,643, (23), had modest (4/iM) affinity for rat uterine oxytocin receptors and very little vasopressin selectivity [71]. A structure activity relationship (SAR) study was carried out around this template, focussing on the toluenesulphonamide group. This work led to the identification of bulky lipophilic substitution as key to improved oxytocin potency, while the introduction of a carboxylic acid group led to improved... 

No Other work has appeared from the Merck group for a number of years and oxytocin receptor antagonism appears to be no longer an active research area for the company. 

A benzodiazepine template was also reported by researchers at GlaxoSmithKline [85]. The lead molecule GW405212, (40), was identified from a 1,296-member library of 1,4-benzodiazepines prepared on Tentagel beads and screened initially in pools of 30 against CHO cells expressing the human oxytocin receptor. It is a highly potent inhibitor of oxytocin binding with a K of 8nM [86]. However, all attempts to improve the pharmacokinetic properties of this molecule were unsuccessful. It appears that the functionality responsible for the oxytocin activity is distributed around the periphery... 

The human oxytocin receptor gene was isolated and characterised in 1994 [122], heralding the development of modern cloned receptor screening. The oxytocin receptor belongs to the Family A series of G-protein coupled 7-transmembrane receptors (GPCRs). A schematic representation of the generic structure of 7TM receptors is shown in Figure 7.3. 

Grazzini E, Guillon G, Mouillac B, Zingg HH. Inhibition of oxytocin receptor function by direct binding of progesterone. Nature 1998 392 509-512. 

Progesterone produces direct membrane effects [16]. These include actions that promote maturation of spermatozoa as well as oocytes and facilitation of the release of neurotransmitters such as dopamine and LH-releasing hormone (LHRH) (Fig. 52-7). Membrane actions of progesterone also activate oxytocin receptors in the hypothalamus in a way that enables oxytocin to turn on sexual behavior in the estrogen-primed female rat [3],... 

None of these findings undermines the importance of the intracellular genomic actions of steroids. Rather, they increase the richness of the cellular actions of steroid hormones and raise the possibility that there may be connections between genomic and nongenomic actions of steroids. For example, genomic action may induce receptors that mediate nongenomic effects. Moreover, the activation of oxytocin receptors by progesterone is dependent... 

Insel, T. R., and Shapiro, L. 1992. Oxytocin receptor distribution reflects social organization in monogamous and polygamous voles. Proceedings of the National Academy of Sciences 89 5981—5985. 

This scaffold recently gained high attention since compound GSK-221149A currently underwent advanced clinical trials as an oxytocin receptor antagonist... 

Extensive medicinal chemistry optimization of potency, selectivity pharmacokinetic, and pharmacodynamic properties finally led to potent, selective, and orally bioavailable GSK-221149A, which is synthesized as shown on Scheme 17 [35, 37, 38]. Peptidic oxytocin receptor antagonists are currently used to treat preterm labor, the main reason for infant death. The peptide derivatives by their nature are not orally bioavailable but must be administered i.v. Surprisingly, the peptide derivatives are less potent and less selective against several related receptors than GSK-221149A with half the molecular weight [39]. 

Leach CA, Liddle J, Peace S, Philp J, Smith lED, Terrell LR, Zhang J (2006) Preparation of l,6-disubstituted-(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-2,5-piperazinedione derivatives as oxytocin receptor antagonists for the treatment of pre-term labor, dysmenorrhea and endometriosis. PCT Int Appl WO 2006067462 Al 20060629... 

Borthwick AD, Hickey DMB, Liddle J, Mason AM (2006) Preparation of diketopiperazines as oxytocin receptor antagonists. 2005-EP6760 W02006000399, 20050621... 

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